The processes used almost exclusively for generating defined solid phases of molecular solids are based on crystallization and/or precipitation from solutions, suspensions or dispersions. This is usually done as one of the last purification steps after the synthesis of the appropriate compounds. However, the crystallization conditions/precipitation conditions are also frequently varied in a controlled manner in order to prepare certain polymorphic modifications or amorphous phases of the compounds used in a pure phase or in the form of mixtures of different phases.
Phases shall be understood here to mean not only polymorphs of a chemical compound; instead, also included are pseudopolymorphs (solvates, hydrates), adducts, complexes, salts, cocrystals, which may be present in various phases.
It is also known that phase transformations can be influenced by thermal and/or mechanical conditions. For example, there is a targeted search for metastable phases under defined thermal conditions, for example in highly supercooled melts or by repeated melting and cooling. These processes find use only on the microscale and have therefore to date been, if anything, of scientific interest.
The literature discloses that, specifically in the preparation of medicaments, partial phase transformations are observed time and again in the formulation of the active ingredients and excipients. Particularly in the formulation of the active ingredients, for example, partial phase transformations are a common complaint. This is the case especially when the phase transformation proceeds in an unwanted manner and/or only partially. What are particularly problematic are phase transformations when the product specification is altered inadvertently and the processability, bioavailability, etc., of the corresponding compounds is influenced unfavorably.
The preparation of stable solid phases of molecular compounds is of great significance for various reasons. This is because different crystal forms possess different physical, chemical and biological properties. For example, the thermal properties (melting point, decomposition temperature), the solubility, the stability, the grinding behavior, the compressibility, the bioavailability, the density, the optical properties (NLO properties, color, fluorescence), magnetic properties, the chemical reaction behavior and, for example, the hydrolysis rate can differ significantly from one another.
To date, molecular solids (molecular crystalline or amorphous phases) have been prepared almost exclusively via the route of crystallization and/or precipitation from solutions, suspensions, dispersion, solvent mixtures or mixtures thereof, and also by lyophilization. A great disadvantage of these processes, specifically in the industrial scale sector, is that large amounts of solvents are obtained in the processes. Moreover, crystal solvates or solvate adducts are formed very frequently and can restrict the usability of the compounds. Particularly in the field of the medicaments industry, there is an interest in producing active ingredients and excipients in stable and solvent-free form.
For the medicaments industry, the preparation of stable phases is particularly relevant, in order to ensure reproducible, lasting product specifications.
In the foods and dyes industry too, there is a need for stable, environmentally friendly, solvent-free and preferably loss-free processes for preparing molecular crystalline phases of the particular compounds; particularly for preparing stable molecular phases.
For health reasons, economic reasons and for reasons of environmental protection, there is therefore a need for a widely applicable stable process which is suitable for phase transformation in molecular solids.